Alzheimer's disease (AD), which is the single major cause of dementia in adults in industrialized societies, is a degenerative brain disorder characterized clinically by a progressive loss of memory, confusion, dementia and ultimately death. Histopathologically, Alzheimer's disease is characterized by the presence in the neocortex, especially the hippocampus, of two brain lesions: the neurofibrillary tangles (NFTs) of paired helical filaments (PHF) in the neurons and the neuritic (senile) plaques in the extracellular space. The formation of senile plaques is related to the appearance of the symptoms and signs of the disease, including amnesia. After the formation of senile plaque, neurofibrillary tangles are produced in the neuronal bodies. The formation of neurofibrillary tangles is related to the worsening of amnesia and of the other symptoms of dementia.
A major component of the senile plaques is amyloid deposits. Cataract is a disease often occurring together with Alzheimer's disease. It is located in the eyes and is also caused by amyloid deposits. Therefore, the treatment of patients having Alzheimer's disease disclosed in the present description and claims may equally be used to treat cataract. As used in the present description and claims, the term Alzheimer's disease, therefore, also include the disease cataract.
A main component of the amyloid deposits is a polypeptide referred to herein as Aβ (Amyloid-beta). Aβ is normally a soluble component of the cerebrospinal fluid where it is found in concentrations of about 3-5 nm. Aβ may have 39 to 43 amino acids, typically 40 amino acids, in the mature form and is derived as a proteolytic cleavage product from a cell surface protein called the amyloid precursor protein (APP) (Kang et al. 1987, Nature 325:733-736):
Many studies have shown that Aβ is toxic in vitro when added directly to neuronal cell cultures (Yankner B A, Duffy L K, Kirschner D A, Science 1990, 250 (4978): 279-282; Koh J Y, Yang L L, Cotman C W, Brain Res 1990, 533 (2): 315-320; and Pike C J, Burdick D, Walencewicz A J, Glabe C G, Cotman C W, J. Neurosci 1993, 13(4):1676-1687).
The neurotoxicity of AS has been located to be in the peptide sequence between amino acid residues 25 and 35 (Aβ(25-35)). Aβ(25-35) induces neuronal cell death equally potent as full length Aβ(1-40) (Yankner B A, Duffy L K, Kirschner D A, Science 1990, 250 (4978): 279-282). The normal function of Aβ is not known at present but might be to form cation selective channels across cell membranes (Kawahara M. et al., 1997, Biophysical Journal 73/1, 67-75).
The precipitation of synthetic Aβ has been shown to be caused by several environmental factors including low pH, high salt concentrations and the presence of metals, e.g. zinc, copper, and mercury (Bush, A. I. et al., 1995, Science 268: 1921-1923). It has been reported that Aβ itself specifically and saturable binds zinc with a high affinity binding (KD=107 nM) at a molar ratio of 1:1 (zinc: Aβ) (Bush, A. I. et al., 1994, J. Biol. Chem. 269: 12152-12158). This binding takes place at physiological concentrations of zinc (Bush, A. I. et al., 1994, Science 265: 1464-1467).
There is a strong supposition that removal of amyloid deposits from patients suffering from Alzheimer's disease will alleviate the symptoms of Alzheimer's disease. Therefore, several attempts have been made to prepare such a drug, as methods for healing Alzheimer's disease are urgently sought.
International Patent Application, publication No. WO 93/10459, discloses a method for the treatment of Alzheimer's disease by administering a zinc binding agent. As preferred compounds, phytic acid, desferri-oximine, sodium citrate, EDTA, 1,2-diethyl-3-hydroxypyridine-4-one, and 1-hydroxyethyl-3-hydroxy-2-methylpyridine-4-one are mentioned.
German patent application No. DE 39 32 338 discloses the use of an aluminium chelator, such as 8-hydroxyquinoline, for the treatment of Alzheimer's disease.
U.S. Pat. No. 5,373,021 discloses the use of disulfiram and its salts and analogs. According to this patent, the disclosed compounds may be used to reduce neurological damage caused by Alzheimer's disease.
International Patent Application, publication No. WO 98/06403 discloses the use of clioquinol for the manufacture of a pharmaceutical composition for the treatment of Alzheimer's disease.
The hitherto known compounds suggested for the treatment of Alzheimer's disease have several drawbacks, which has prevented their widespread use. Most of the compounds are unable to penetrate the blood-brain-barrier and thus cannot readily reach the areas in which the amyloid is deposited. Disulfiram, which may penetrate the blood-brain-barrier, has the drawback that, when it is combined by a patient with ethyl alcohol, it causes severe adverse reactions, including headaches, nausea, vomiting, sweating, thirst, weakness, and low blood pressure. Cliquinol (5-chloro-7-iodo-8-hydroxyquinoline), which also may penetrate the blood-brain-barrier, has a damning history as it as a side effect causes subacute myelo-optico-neuropathy (SMON).
Phanquinone (4,7-phenanthroline-5,6-dione) has hitherto been used for the treatment of various disorders, such as amoebiasis. Phanquinone has been sold by CIBA-GEIGY under the trademark ENTOBEX. In contrast to clioquinol no adverse side effects have been detected when phanquinone is used in the normal dosage range.
In the past an antiamebic pharmaceutical preparation containing both clioquinol and phanquinone has been sold by CIBA GEIGY under the trademark Mexafor. However, the marketing of this preparation was stopped when it was realized that clioquinol caused SMON.